Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study.
The antidepressant activity of citalopram (R,S-CIT) is mainly due to its (S)-enantiomer (S-CIT). P-glycoprotein (P-gp), encoded by the ABCB1 gene, is a membrane transport protein which regulates the efflux of many drugs. Polymorphisms in the ABCB1 gene may have an impact on the expression and function of P-gp, thereby influencing the response to treatment with antidepressants, which are substrates of this protein. The influence of ABCB1 polymorphism on the disposition of R,S-CIT in plasma and cerebrospinal fluid (CSF) was examined under steady-state conditions in 15 patients with major depression treated with 40 mg/d R,S-CIT for 4 weeks. In contrast to the ABCB1 C3435T polymorphism, only the ABCB1 G2677T polymorphism significantly influences R,S-CIT plasma and CSF concentrations (46+/-11 ng/ml versus 69+/-20 ng/ml for TT versus GT/GG in plasma, p=0.027; 24+/-5 ng/ml versus 32+/-9 ng/ml for TT versus GT/GG in CSF, p=0.05). On the other hand, no significant influence of G2677T polymorphism was found on the plasma and CSF (S)/(R) ratio, suggesting a lack of stereoselectivity in the activity of this transporter. The 2677 GG/GT genotype was associated with a better treatment response (p=0.001) compared with 2677TT genotype. Furthermore, higher R,S-CIT plasma and CSF concentrations were observed in treatment responders. This study is the first to demonstrate that a P-gp polymorphism significantly influences plasma and CSF concentrations of R,S-CIT in depressive patients, therefore possibly influencing the activity of this antidepressant. These findings should be replicated in future studies with larger groups of patients. Because of the small number of subjects in the present study, future studies with larger groups of patients, also with different ethnicities.
Nikisch
Georg
G
Department of Psychiatry and Psychotherapy, Klinikum Fulda gAG, Pacelliallee 4, 36043 Fulda, Germany. georg.nikisch@klinikum-fulda.de
Eap
Chin B
CB
Baumann
Pierre
P
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D015283:Citalopram / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D003627:Data Interpretation, Statistical; D003865:Major Depressive Disorder / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D013237:Stereoisomerism; D055815:Young Adult
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015283:Citalopram; D017367:Selective Serotonin Reuptake Inhibitors; C513055:ABCB1 protein, human